The purpose of the proposed project is to mount a multi-faceted attack on the contribution of the blood vessel to thrombogenesis. Four main factors will be considered: hemostatic reactivity of the intimal connective tissue; conformational changes in the vessel wall leading to local flow disturbances; cellular distribution of tissue factor (thromboplastin); and liability of endothelial cells to detachment. The relative contribution of these factors will be evaluated in normal blood vessels of different locations and under the influence of different endocrine environments and in pathological vessels. Particular attention will be given to the vessel in experimental arteriosclerosis. We have produced this lesion by balloon-induced intimal injury, where healing is accompanied by massive intimal hypertrophy. The thrombogenic potential of this lesion will be evaluated by new techniques recently developed in our laboratory, and attempts will be made to moderate the healing response. A special problem to be considered will be that of delayed vessel graft failure. Our hypothesis states that this complication follows hypertrophy at the junction lines, with local conditions favoring thrombosis at those sites. Attempts will be made to moderate this lesion. A device will be developed which is capable of monitoring platelet deposition in tubes and containers, so that the contribution of flow alterations and the nature of the reacting surface can be readily and quantitatively evaluated. Finally, a clinical study will be undertaken to assess the value of circulating endothelial cells in the prediction of thrombotic disease. The first aspect of this study will be to improve detection methods so that the test can be more clinically feasible. This will be followed by prospective clinical studies to ascertain the diagnostic value of the test.